A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment
Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its un...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223014348 |
| _version_ | 1797630662640926720 |
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| author | Fang-Ching Chao Eloísa Berbel Manaia Gilles Ponchel Chien-Ming Hsieh |
| author_facet | Fang-Ching Chao Eloísa Berbel Manaia Gilles Ponchel Chien-Ming Hsieh |
| author_sort | Fang-Ching Chao |
| collection | DOAJ |
| description | Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique pharmacokinetic behavior (e.g. high volume of distribution and affinity to extra-plasma tissue compartments), we proposed a modified PBPK model structure and developed the model with multispecies extrapolation to compensate for the limitation of obtaining clinical tissue data. Our model predicted the disposition of doxorubicin in multiple tissues including clinical tissue data with an overall absolute average fold error (AAFE) of 2.12. The model’s performance was further validated with 8 clinical datasets in combined with intracellular doxorubicin concentration with an average AAFE of 1.98. To assess the potential cellular toxicity, toxicity levels and area under curve (AUC) were defined for different dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of doxorubicin in multiple organ sites associated with commonly observed adverse effects (AEs) were simulated and calculated the AUC for quantitative assessments. Our findings supported the clinical dosing regimen of 75 mg/m2 with a 21-day interval and suggest that slow infusion and separated single high doses may lower the risk of developing AEs from a cellular level, providing valuable insights for the risk assessment of doxorubicin chemotherapy. In conclusion, our work highlights the potential of PBPK modelling to provide quantitative assessments of cellular toxicity and supports the use of clinical dosing regimens to mitigate the risk of adverse effects. |
| first_indexed | 2024-03-11T11:11:22Z |
| format | Article |
| id | doaj.art-39991fef80c34e1191d6c48f6f7edb3f |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T11:11:22Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-39991fef80c34e1191d6c48f6f7edb3f2023-11-12T04:38:43ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-12-01168115636A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessmentFang-Ching Chao0Eloísa Berbel Manaia1Gilles Ponchel2Chien-Ming Hsieh3CNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay 91400, FranceCNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay 91400, FranceCNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay 91400, France; Correspondence to: CNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, 17 avenue des Sciences, Orsay 91400, France.School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; Correspondence to: School of Pharmacy, College of Pharmacy, Taipei Medical University & D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing Street, Taipei City 11031, Taiwan.Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique pharmacokinetic behavior (e.g. high volume of distribution and affinity to extra-plasma tissue compartments), we proposed a modified PBPK model structure and developed the model with multispecies extrapolation to compensate for the limitation of obtaining clinical tissue data. Our model predicted the disposition of doxorubicin in multiple tissues including clinical tissue data with an overall absolute average fold error (AAFE) of 2.12. The model’s performance was further validated with 8 clinical datasets in combined with intracellular doxorubicin concentration with an average AAFE of 1.98. To assess the potential cellular toxicity, toxicity levels and area under curve (AUC) were defined for different dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of doxorubicin in multiple organ sites associated with commonly observed adverse effects (AEs) were simulated and calculated the AUC for quantitative assessments. Our findings supported the clinical dosing regimen of 75 mg/m2 with a 21-day interval and suggest that slow infusion and separated single high doses may lower the risk of developing AEs from a cellular level, providing valuable insights for the risk assessment of doxorubicin chemotherapy. In conclusion, our work highlights the potential of PBPK modelling to provide quantitative assessments of cellular toxicity and supports the use of clinical dosing regimens to mitigate the risk of adverse effects.http://www.sciencedirect.com/science/article/pii/S0753332223014348Physiologically-based pharmacokineticsDoxorubicinInterspecies extrapolationDispositionQuantitative pharmacologyToxicity |
| spellingShingle | Fang-Ching Chao Eloísa Berbel Manaia Gilles Ponchel Chien-Ming Hsieh A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment Biomedicine & Pharmacotherapy Physiologically-based pharmacokinetics Doxorubicin Interspecies extrapolation Disposition Quantitative pharmacology Toxicity |
| title | A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment |
| title_full | A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment |
| title_fullStr | A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment |
| title_full_unstemmed | A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment |
| title_short | A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment |
| title_sort | physiologically based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment |
| topic | Physiologically-based pharmacokinetics Doxorubicin Interspecies extrapolation Disposition Quantitative pharmacology Toxicity |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223014348 |
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